Kursk state medical university

• Name:Dalhatu Saidu

• Group:31

• Year:2nd year 4th

semester

Department:microboilogy

•Viral encephalitis

Introduction

• Encephalitis is an acute inflammatory process affecting the brain

• Viral infection is the most common and important cause, with over 100 viruses implicated worldwide

• Symptoms • Fever

• Headache

• Behavioral changes

• Altered level of consciousness

• Focal neurologic deficits

• Seizures

• Incidence of 3.5-7.4 per 100,000 persons per year

Causes of Viral Encephalitis

• Herpes viruses – HSV-1, HSV-2, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, human herpes virus 6

• Adenoviruses• Influenza A• Enteroviruses, poliovirus• Measles, mumps, and rubella viruses• Rabies• Arboviruses – examples: Japanese encephalitis; St. Louis

encephalitis virus; West Nile encephalitis virus; Eastern, Western and Venzuelan equine encephalitis virus; tick borne encephalitis virus

• Bunyaviruses – examples: La Crosse strain of California virus• Reoviruses – example: Colorado tick fever virus• Arenaviruses – example: lymphocytic choriomeningitis virus

What Is An Arbovirus?

• Arboviruses = arthropod-borne viruses

• Arboviruses are maintained in nature through biological transmission between susceptible vertebrate hosts by blood-feeding arthropods

• Vertebrate infection occurs when the infected arthropod takes a blood meal

http://www.cdc.gov/ncidod/dvbid/arbor/schemat.pdf

Major Arboviruses That Cause Encephalitis• Flaviviridae

• Japanese encephalitis

• St. Louis encephalitis

• West Nile

• Togaviridae• Eastern equine encephalitis

• Western equine encephalitis

• Bunyaviridae• La Crosse encephalitis

History of West Nile Virus

• 1937 - West Nile virus isolated from woman in Uganda

• 1950s – First recorded epidemics in Israel (1951-1954, 1957)

• 1962 – Epidemic in France

• 1974 – Epidemic in South Africa. Largest ever West Nile epidemic.

• 1996 – Romanian epidemic with features similar to those of the North American outbreak. 500 cases and 50 deaths.

• 1999 – Russian outbreak. 40 deaths.

History of St. Louis Encephalitis• 1933 – virus isolated during St. Louis and Kansas

City, MO epidemic

• 1940’s – virus spread to Pacific Coast

• 1959-1971 – virus spread to Southern Florida

• 1974-1977 – last major epidemic. Over 2,500 cases in 35 states.

• 1990-1991 – South Florida epidemic. 226 cases and 11 deaths.

• 1999 – New Orleans outbreak. 20 reported cases.

History of Japanese Encephalitis• 1800s – recognized in Japan• 1924 – Japan epidemic. 6125 cases, 3797 deaths• 1935 – virus isolated in brain of Japanese patient

who died of encephalitis• 1938 – virus isolated from Culex mosquitoes in

Japan• 1948 – Japan outbreak• 1949 – Korea outbreak• 1966 – China outbreak• Today – extremely prevalent in South East Asia.

30,000-50,000 cases reported each year.

History of Western Equine Encephalitis• Early 1900’s – epizootics of viral encephalitis in horses

described in Argentina

• 1912 – 25,000 horses died in Central Plains of US

• 1930 – San Joaquin Valley, CA outbreak. 6000 cases in horses. Virus isolated from horse brains

• 1938 – virus isolated from brain of a child

Flavivirus• Japanese Encephalitis Virus• St. Louis encephalitis virus• West Nile Virus

Flavivirus: Virus Classification• Family Flaviviridae

• 3 Genera

• Flavivirus, Pestivirus, Hepacivirus

• Flavivirus - 12 Serogroups

• Japanese encephalitis virus serogroup

• Includes West Nile Virus (WNV), St. Louis Encephalitis, and others

Viral Replication Cycle

Genome Structure

Viral Genome

• Positive Strand RNA Genome

• 1 ORF – Genome encodes single polyprotein which is subsequently cleaved• 5’ portion

• 3 structural proteins

• 3’ portion• 7 non-structural proteins

• Genome also includes 5’ and 3’ noncoding regions which have functional importance

Viral Proteins: Structural and Non-Structural• Structural Proteins• Capsid (C), Membrane (M), Envelope (E)

• The envelope - receptor binding • Dimers of E protein arrange their β sheets in a head to

tail formation which lie flat on top of the lipid bilayer. The distal portions of these proteins are anchored in the membrane

• Non-Structural Multifunctional Proteins• NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5

• Many functions of non-structural proteins have yet to be determined

Viral Non-Structural Proteins

• NS1- may play a role in flavivirus RNA synthesis; it has been shown to be essential for negative strand synthesis

• NS2A, NS2B, NS4A, NS4B - may facilitate the assembly of viral replication complexes by an unknown mechanism

• NS3: Multifunctional

• Proteolytic function upon association with NS2B

• RNA triphosphatase function thought to be important for the synthesis of the 5’ cap structure

• Helicase and NTPase activity

• Its activity may be upregulated through interaction with phosphorylated NS5

• NS5• RNA dependent RNA polymerase

• Methyltransferase domain thought to be required for formation of the 5’ cap

Togavirus

• Eastern Equine Encephalitis Virus• Western Equine Encephalitis Virus• Venezuelan Equine Encephalitis Virus

Togavirus

• Family: Togaviridae• Genus: Alphavirus

• 49S Single Stranded Genome• ~11700 Nucleotides

• 3’ end: Five potential structural proteins• C, E3, E2, 6K, and E1

• 5’ end: Unknown number of non-structural proteins probably involved in replication

• Genome has an opposite orientation from the Flaviviruses

Alphavirus Structure

http://www.cdc.gov/ncidod/dvbid/arbor/alphavir.htm

Alphaviruses: Protein Function

• E1and E2 glycoprotein heterodimers form trimers that appear as knobs on the surface of the virion• E1 – transmembrane glycoprotein with 2 to 3 N-linked

glycosylation sites• E2 - glycoprotein with 1 to 2 N-linked glycosylation sites, contains

short intracytoplasmic tail and hydrophobic stretch of amino acids that serves as the fusion peptide for viral entry

• Capsid protein has a conserved N-terminal region which binds RNA and a C-terminal region which interacts with the cytoplasmic tail of E2 as well as capsid proteins

• E3 and 6K proteins are signal sequences for E2 and E1, respectively, and are largely cleaved off from the mature virion

BunyaviridaeLa Crosse Virus

La Crosse Virus

http://www.virology.net/Big_Virology/BVRNAbunya.html

Bunyaviruses

• Genome - single strand of negative sense RNA

• Four structural proteins• Two external proteins

• Two associated with RNA to form nucleocapsid

• Matrix proteins absent from Bunyaviruses, therefore capsid proteins and envelope glycoproteins directly interact prior to budding

Initial Signs

• Headache

• Malaise

• Anorexia

• Nausea and Vomiting

• Abdominal pain

Developing Signs

• Altered LOC – mild lethargy to deep coma.

• AMS – confused, delirious, disoriented.

• Mental aberrations: • hallucinations

• agitation

• personality change

• behavioral disorders

• occasionally frank psychosis

• Focal or general seizures in >50% severe cases.

• Severe focused neurologic deficits.

Neurologic Signs

• Virtually every possible focal neurological disturbance has been reported.

• Most Common

• Aphasia

• Ataxia

• Hemiparesis with hyperactive tendon reflexes

• Involuntary movements

• Cranial nerve deficits (ocular palsies, facial weakness)

Other Causes of Encephalopathy• Anoxic/Ischemic conditions• Metabolic disorders• Nutritional deficiency• Toxic (Accidental & Intentional)• Systemic infections• Critical illness• Malignant hypertension• Mitochondrial cytopathy (Reye’s and MELAS syndromes)• Hashimoto’s encephalopathy• Traumatic brain injury• Epileptic (non-convulsive status)• CJD (Mad Cow)

Differential Diagnosis

• Distinguish Etiology• (1) Bacterial infection and other infectious conditions

• (2) Parameningeal infections or partially treated bacterial meningitis

• (3) Nonviral infectious meningitides where cultures may be negative (e.g., fungal, tuberculous, parasitic, or syphilitic disease)

• (5) Meningitis secondary to noninfectious inflammatory diseases

• MRI• Can exclude subdural bleeds, tumor, and sinus thrombosis

• Biopsy • Reserved for patients who are worsening, have an undiagnosed

lesion after scan, or a poor response to acyclovir.

• Clinical signs cannot distinguish different viral encephalitides

Clinical ConsiderationsRadiology

MRI

Clinical ConsiderationsLaboratory Diagnosis

Laboratory Diagnosis

• Diagnosis is usually based on CSF

• Normal glucose

• Absence of bacteria on culture.

• Viruses occasionally isolated directly from CSF

• Less than half are identified

• Polymerase Chain Reaction techniques

• Detect specific viral DNA in CSF

NYSDOH PCRNEW YORK STATE DEPARTMENT OF HEALTH (NYSDOH)

Viral Encephalitis Letter of Agreement forPhysician Ordered Testing by Polymerase Chain Reaction (PCR)

NYSDOH's Wadsworth Center offers the following tests on CSF for viral encephalitis:PCR testing for a panel of viruses, including: herpes simplex, varicella zoster, cytomegalovirus, Epstein-Barr virus, enteroviruses, St. Louis encephalitis (SLE), eastern equine encephalitis (EEE), California encephalitis (including LaCrosse and Jamestown Canyon viruses), Powassan and West Nile (WN) viruses, andEnzyme-linked immunoassay (ELISA) for WN virus.If there is insufficient quantity of CSF (less than 1.0 ml) to conduct both ELISA and PCR for WN virus, please consider the following in determining which test is most appropriate for your patient:ELISA is more sensitive than PCR for WN viral testing and should be considered when there is stronger suspicion of WN virus than other viruses. PCR is less sensitive for WN virus, but tests for a wide range of viruses. PCR should be considered if viruses other than WN virus are suspected.

Please note your testing priority below or on the viral encephalitis/meningitis case report form. If PCR testing is desired, the agreement below must be completed.

Viral Encephalitis PCR Panel West Nile Virus ELISA Antibody Testing

Clinical ConsiderationsDisease Progression

Disease Progression

• Worsening neurologic symptoms

• Vascular collapse and shock

• May be due to adrenal insufficiency.

• Loss of tissue fluid may be equally important.

• Homeostatic failure

• Decreased respiratory drive

Treatment

• When HSE cannot be ruled out, Acyclovir must be started promptly (before the patient lapses into coma) and continued at least 10 days for maximal therapeutic benefit.

• Rocky Mountain spotted fever should also be considered, and empiric treatment with Doxycycline is indicated.

Suspected HSE Treatment Plan

Acyclovir

• Acyclovir is a synthetic purine nucleoside analogue with inhibitory activity against HSV-1 and HSV-2, varicella-zoster virus (VZV), Epstein-Barr virus (EBV) and cytomegalovirus (CMV)

• In order of decreasing effectiveness

• Highly selective

Acyclovir Action

• Thymidine Kinase (TK) of uninfected cells does not use acyclovir as a substrate.

• TK encoded by HSV, VZV and EBV2 converts acyclovir into acyclovir monophosphate.

• The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes.

• Acyclovir triphosphate interferes with Herpes simplex virus DNA polymerase and inhibits viral DNA replication.

• Acyclovir triphosphate incorporated into growing chains of DNA by viral DNA polymerase.

• When incorporation occurs, the DNA chain is terminated.• Acyclovir is preferentially taken up and selectively converted to the

active triphosphate form by HSV-infected cells. • Thus, acyclovir is much less toxic in vitro for normal uninfected cells

because: 1) less is taken up; 2) less is converted to the active form.

Supportive Therapy

• Fever, dehydration, electrolyte imbalances, and convulsions require treatment.

• For cerebral edema severe enough to produce herniation, controlled hyperventilation, mannitol, and dexamethasone.• Patients with cerebral edema must not be overhydrated.• If these measures are used, monitoring ICP should be considered.

• If there is evidence of ventricular enlargement, intracranial pressure may be monitored in conjunction with CSF drainage.• Outcome is usually poor.• For infants with subdural effusion, repeated daily subdural taps through

the sutures usually helps. • No more than 20 mL/day of CSF should be removed from one side to

prevent sudden shifts in intracranial contents. • If the effusion persists after 3 to 4 weeks of taps, surgical exploration for

possible excision of a subdural membrane is indicated.

Dexamethasone

• Synthetic adrenocortical steroid

• Potent anti-inflammatory effects

• Dexamethasone injection is generally administered initially via IV then IM

• Side effects: convulsions; increased ICP after treatment; vertigo; headache; psychic disturbances

Prognosis

• The mortality rate varies with etiology, and epidemics due to the same virus vary in severity in different years. • Bad: Eastern equine encephalitis virus infection, nearly 80% of

survivors have severe neurological sequelae.

• Not so Bad: EBV, California encephalitis virus, and Venezuelan equine encephalitis virus, severe sequelae are unusual.

• Approximately 5 to 15% of children infected with LaCrosse virus have a residual seizure disorder, and 1% have persistent hemiparesis.

• Permanent cerebral sequelae are more likely to occur in infants, but young children improve for a longer time than adults with similar infections. • Intellectual impairment, learning disabilities, hearing loss, and

other lasting sequelae have been reported in some studies.

Vaccination

• None for most Encephalitides

• JE• Appears to be 91% effective

• There is no JE-specific therapy other than supportive care

• Live-attenuated vaccine developed and tested in China • Appears to be safe and effective

• Chinese immunization programs involving millions of children

• Vero cell-derived inactivated vaccines have been developed in China• 2 millions doses are produced annually in China and Japan

• Several other JE vaccines under development

Public Health ConsiderationsEndemic Prevention

Infection Control

• CDC’s “Three Ways to Reduce your West Nile Virus Risk”

• Avoid mosquito bites

• Mosquito-proof your home

• Help your community

Community-Wide Efforts

• Clean Up Breeding Grounds

• Ensure Safe Blood Supply

• Mosquito Control Programs

• Controversial

• Surveillance

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Personal Protection

• Make sure window and door screens are "bug tight"

• Replace your outdoor lights with yellow "bug" lights

• Bug zappers are not very effective

• ULV foggers for backyard use

• Keep vegetation and standing water in check around the dwelling

Thank you

spasiba